LifePharms, Inc. has established a collection of >12,000 unique species of basidiomycetes/ascomycetes, and the Natural Products Laboratory of Research Triangle Institute has a long and successful history of isolating potent antitumor agents from natural sources. By teaming our respective capabilities, we propose to 1) screen the LifePharms Inc., repository of basidiomycetes and ascomycetes for bioactivity against 9KB cells; 2) prioritize the samples based upon reconfirmation of activity, literature, availability of fungi, etc.; 3) obtain larger samples of the confirmed bioactive fungal species, 4) fractionate and purify the bioactive compounds from these larger samples using a bioassay guided approach; 5) characterize the pure bioactive compounds completely; 6) evaluate the bioactivity of the pure compounds in topoisomerase I inhibition and DNA nicking assays, as well as, measure EC50 values vs. 9KB cells; 7) scale up the isolation procedures in order to provide an ample quantity of pure compound for in vivo studies. Synthetic methodologies will be pursued for both total and analog synthesis of the bioactive compounds. (Phase II); 8) test the compounds for in vivo activity. (Phase II). PROPOSED COMMERCIAL APPLICATIONS: The National Cancer Institute estimated nearly 1.3 million new cases of cancer in 1998 and over one-half million deaths. Cancer has a mortality rate of about 160 deaths per 100,000 population, and the death rates are increasing at about 6% annually. The United States spends approximately $7-8 billion annually on pharmacological cancer therapies alone. For many forms of cancer, the 5-year survival rate is very low. Consequently, novel anticancer agents are needed urgently.